Human Gene LEP (ENST00000308868.5_3) from GENCODE V45lift37
Description: Homo sapiens leptin (LEP), mRNA. (from RefSeq NM_000230) RefSeq Summary (NM_000230): This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Gencode Transcript: ENST00000308868.5_3 Gencode Gene: ENSG00000174697.5_6 Transcript (Including UTRs) Position: hg19 chr7:127,881,331-127,897,682 Size: 16,352 Total Exon Count: 3 Strand: + Coding Region Position: hg19 chr7:127,892,072-127,894,816 Size: 2,745 Coding Exon Count: 2
ID:LEP_HUMAN DESCRIPTION: RecName: Full=Leptin ; AltName: Full=Obese protein; AltName: Full=Obesity factor; Flags: Precursor; FUNCTION: Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:17344214, PubMed:15899045, PubMed:19688109). In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo- pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:8589726, PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption (PubMed:24340098). Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689). SUBUNIT: Interacts with SIGLEC6. INTERACTION: P41159; O75031: HSF2BP; NbExp=3; IntAct=EBI-12994693, EBI-7116203; SUBCELLULAR LOCATION: Secreted TISSUE SPECIFICITY: Adipose tissue is the main source of leptin. It is also produced by other peripheral tissues such as the skeletal muscle (PubMed:7789654, PubMed:16052473, PubMed:12448771). Expressed by intercalated and striated tracts of submandibular and parotid salivary gland intralobular ducts (PubMed:12448771). Detected by fundic epithelium of the gastric mucosa (PubMed:10896907). Secreted into blood and gastric juice (PubMed:10896907). INDUCTION: Induced by secretin. DISEASE: Leptin deficiency (LEPD) [MIM:614962]: A rare disease characterized by low levels of serum leptin, severe hyperphagia and intractable obesity from an early age. te=The disease is caused by variants affecting the gene represented in this entry. SIMILARITY: Belongs to the leptin family. WEB RESOURCE: Name=Wikipedia; Note=Leptin entry; URL="https://en.wikipedia.org/wiki/Leptin"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/lep/";
age of menarche Comings DE et al. 2001, The LEP gene and age of menarche: maternal age as a potential cause of hidden stratification in association studies., Molecular genetics and metabolism. 2001 Jul;73(3):204-10.
[PubMed 11461187]
There was a significant (P or =30 years. If maternal age effects prove to be generalized, failure to take them into consideration could provide a source of hidden stratification that could significantly alter the replication of association studies.
BMI McGarvey ST 2002, Human leptin locus (LEP) alleles and BMI in Samoans., International journal of obesity and related metabolic disorders. 2002 Jun;26(6):783-8.
[PubMed 12037648]
These findings indicate that the leptin 3'-tetranucleotide repeat is associated with high BMI in adult Samoans, with allele 226 having a low frequency in the high BMI group.
body mass McGarvey, S. T. et al. 2002, Human leptin locus (LEP) alleles and BMI in Samoans., International journal of obesity and related metabolic disorders. 2002 Jun;26(6):783-8.
[PubMed 12037648]
These findings indicate that the leptin 3'-tetranucleotide repeat is associated with high BMI in adult Samoans, with allele 226 having a low frequency in the high BMI group.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P41159
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Gene Ontology (GO) Annotations with Structured Vocabulary
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0001525 angiogenesis GO:0001542 ovulation from ovarian follicle GO:0001666 response to hypoxia GO:0001819 positive regulation of cytokine production GO:0001890 placenta development GO:0001932 regulation of protein phosphorylation GO:0001936 regulation of endothelial cell proliferation GO:0002021 response to dietary excess GO:0003300 cardiac muscle hypertrophy GO:0006006 glucose metabolic process GO:0006111 regulation of gluconeogenesis GO:0006112 energy reserve metabolic process GO:0006114 glycerol biosynthetic process GO:0006629 lipid metabolic process GO:0006635 fatty acid beta-oxidation GO:0006909 phagocytosis GO:0007165 signal transduction GO:0007260 tyrosine phosphorylation of STAT protein GO:0007565 female pregnancy GO:0007584 response to nutrient GO:0007623 circadian rhythm GO:0008203 cholesterol metabolic process GO:0008206 bile acid metabolic process GO:0008217 regulation of blood pressure GO:0008284 positive regulation of cell proliferation GO:0008340 determination of adult lifespan GO:0008343 adult feeding behavior GO:0009062 fatty acid catabolic process GO:0009892 negative regulation of metabolic process GO:0010507 negative regulation of autophagy GO:0010888 negative regulation of lipid storage GO:0014068 positive regulation of phosphatidylinositol 3-kinase signaling GO:0014823 response to activity GO:0019222 regulation of metabolic process GO:0019953 sexual reproduction GO:0021954 central nervous system neuron development GO:0030073 insulin secretion GO:0030217 T cell differentiation GO:0030300 regulation of intestinal cholesterol absorption GO:0031667 response to nutrient levels GO:0032008 positive regulation of TOR signaling GO:0032099 negative regulation of appetite GO:0032310 prostaglandin secretion GO:0032355 response to estradiol GO:0032615 interleukin-12 production GO:0032635 interleukin-6 production GO:0032760 positive regulation of tumor necrosis factor production GO:0032814 regulation of natural killer cell activation GO:0032817 regulation of natural killer cell proliferation GO:0032868 response to insulin GO:0033197 response to vitamin E GO:0033210 leptin-mediated signaling pathway GO:0033686 positive regulation of luteinizing hormone secretion GO:0035360 positive regulation of peroxisome proliferator activated receptor signaling pathway GO:0035556 intracellular signal transduction GO:0035630 bone mineralization involved in bone maturation GO:0035904 aorta development GO:0038108 negative regulation of appetite by leptin-mediated signaling pathway GO:0042102 positive regulation of T cell proliferation GO:0042269 regulation of natural killer cell mediated cytotoxicity GO:0042307 positive regulation of protein import into nucleus GO:0042445 hormone metabolic process GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein GO:0042593 glucose homeostasis GO:0042755 eating behavior GO:0043066 negative regulation of apoptotic process GO:0043270 positive regulation of ion transport GO:0043410 positive regulation of MAPK cascade GO:0044320 cellular response to leptin stimulus GO:0045471 response to ethanol GO:0045598 regulation of fat cell differentiation GO:0045765 regulation of angiogenesis GO:0045906 negative regulation of vasoconstriction GO:0046325 negative regulation of glucose import GO:0046427 positive regulation of JAK-STAT cascade GO:0046628 positive regulation of insulin receptor signaling pathway GO:0046850 regulation of bone remodeling GO:0046881 positive regulation of follicle-stimulating hormone secretion GO:0046890 regulation of lipid biosynthetic process GO:0048639 positive regulation of developmental growth GO:0050790 regulation of catalytic activity GO:0050796 regulation of insulin secretion GO:0050810 regulation of steroid biosynthetic process GO:0050892 intestinal absorption GO:0050901 leukocyte tethering or rolling GO:0050999 regulation of nitric-oxide synthase activity GO:0051541 elastin metabolic process GO:0051726 regulation of cell cycle GO:0051897 positive regulation of protein kinase B signaling GO:0060587 regulation of lipoprotein lipid oxidation GO:0060612 adipose tissue development GO:0061037 negative regulation of cartilage development GO:0070093 negative regulation of glucagon secretion GO:0071298 cellular response to L-ascorbic acid GO:0071300 cellular response to retinoic acid GO:0072604 interleukin-6 secretion GO:0072606 interleukin-8 secretion GO:0090335 regulation of brown fat cell differentiation GO:0098868 bone growth GO:1900015 regulation of cytokine production involved in inflammatory response GO:1900180 regulation of protein localization to nucleus GO:1900745 positive regulation of p38MAPK cascade GO:1904651 positive regulation of fat cell apoptotic process GO:1990051 activation of protein kinase C activity GO:2000379 positive regulation of reactive oxygen species metabolic process GO:2000486 negative regulation of glutamine transport GO:2000491 positive regulation of hepatic stellate cell activation
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
